DESCRIPTION (Verbatim from the Applicant's Abstract): Anesthesia/surgery predisposes the patient to develop nosocomial pneumonia by mechanisms that are not completely defined. The presence of a viral respiratory tract infection (RTI) during anesthesia/surgery further complicates the host antibacterial response. Evidence from our laboratory has demonstrated anesthesia/surgery induces changes in cytokine response (e.g., TNFalpha, MIP-2, IFNgamma), leukocyte recruitment, and lung injury to influenza RTI. These responses are also critical to innate host defenses against bacterial pathogens. Our focus is to examine cellular mechanisms during a viral RTI that predispose the host to a post-surgical bacterial pneumonia. We hypothesize that anesthesia/surgery will change host responses differently during distinct periods in the course of a viral RTI by altering expression of pro- and antiinflammatory cytokines, thereby decreasing antibacterial defenses. Aim #1 will assess the effects of anesthesia/surgery during influenza on bacterial clearance, inflammatory cell influx, and cytokine expression an Escherichia coli challenge. We predict that laparotomy during influenza will promote the relative expression of MCP-1 and IL-10 over TNFalpha, MIP-2, and IFNgamma. Aim #2: will assess ex vivo the combined effect of laparotomy and influenza on a) LPS stimulated aMphi cytokine expression and phagocytic activity, and b) the ability of in vitro antiMCP-1, antiIL-10, or IFNgamma administration to improve M dysfunction. We postulate that laparotomy during influenza will alter aMphi regulatory functions and decrease effector functions as a result of selective enhancement of expression anti-compared to proinflammatory cytokines. Finally, in Aim #3, we will examine the contribution of endogenous cytokines in the suppression of antibacterial defenses following laparotomy during influenza by selective cytokine manipulations. Bacterial clearance, inflammatory cell influx, and cytokine levels will be assessed. We anticipate that neutralization of IL-10 or MCP-1, administration of IFNgamma, or increased TNFalphaexpression will improve antibacterial host defenses following laparotomy during physical signs of influenza. These studies will examine mechanisms that lead to alterations in bacterial clearance post-surgically following a viral RTI, assess the pathogenesis of post-surgical pneumonia in general, and suggest immune adjuvant strategies to prevent this complication.